Human immunodeficiency virus (HIV-1) infection is a serious condition which if left untreated ultimately destroys the host's immune system resulting in acquired immunodeficiency syndrome (AIDS) and premature death. Despite advances in antiretroviral therapies (ART), HIV continues to be a global epidemic and a global public health priority. An estimated 35 million people worldwide were living with HIV in 2012 (Global Report: UNAIDS report on the global AIDS epidemic 2013. UNAIDS/JC2502/1/E). In the U.S., an estimated 1.2 million people are living with HIV and about 50,000 become newly infected each year. HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. More than 650,000 people in the U.S. have died with AIDS and more than 14,000 additional deaths are reported each year. Treatment can help people with HIV live longer, healthier lives, but currently only 30 percent of people with HIV in the U.S. are successfully keeping their virus under control. (Center for Disease Control and Prevention. Today's HIV/AIDS epidemic. July 2015).
Nucleoside reverse transcriptase inhibitors (NRTIs or NsRTIs) inhibit HIV reverse transcriptase and block HIV replication. They are one of 6 classes of HIV antiretrovirals (ARVs) used as components of potent and durable multi-drug regimens that typically combine two NRTIs (or an NRTI with an NtRTI) with a non-nucleoside reverse transcriptase inhibitor, an integrase strand transfer inhibitor, or a protease inhibitor. Combination treatment maximizes treatment response and minimizes the emergence of drug resistance.
Due to the fact that HIV replication is asynchronous, antiretroviral agents need to be continuously present in patients to effectively suppress viremia. For most classes of drugs including protease inhibitors, integrase inhibitors, and non-nucleoside reverse transcriptase inhibitors, efficacy is dictated by circulating drug concentrations and dosing is aimed at providing circulating drug concentrations throughout the dosing interval (i.e. Cmin) that exceed those required to suppress viral replication (i.e. the IC50 or IC95). In contrast, upon entering cells, NRTIs and nucleotide reverse transcriptase inhibitors (NtRTIs such as tenofovir) enter into obligate intracellular anabolic pathways for conversion to active phosphorylated forms, and it is their intracellular half-lives rather than their plasma concentrations that dictate their persistent effect. All currently approved NRTIs and NtRTIs are administered at least once-daily.
4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor that blocks HIV-1 and SIV viral replication in vitro (Kawamoto, A., Kodama, E., Sarafianos S. F. et al, Int. J. Biochem. Cell Biol.; 40(11):2410-20 [2008]; Ohrui, H., Kohgo, S., Hayakawa, H. et al, Nucleosides, Nucleotides & Nucleic Acids, 26, 1543-1546 [2007]) and in vivo (Hattori, S., Ide, K., Nakata, H. et al. Antimicrobial. Agents and Chemotherapy, 53, 3887-3893 [2009]).
U.S. Pat. No. 7,339,053 describes EFdA (referred to in the '053 patent as 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine) and 4′-ethynyl-2-chloro-2′-deoxyadenosine (referred to herein as ECdA; referred to in the '053 patent as 2-chloro-2′-deoxy-4′-C-ethynyladenosine). EFdA and ECdA have the following chemical structures:
Both compounds are metabolized in cells to their active triphosphate anabolite which inhibits HIV reverse transcriptase. In contrast to NsRTIs and NtRTI's currently available for the treatment of HIV infection, which lack a 3′-OH group to block incorporation of incoming nucleotide, EFdA and ECdA retain a 3′-OH group and act as a chain terminator by preventing translocation of the primer:template in the reverse transcriptase (RT) active site and preventing binding of incoming deoxyribonucleotides triphosphates (dNTPs). In addition, the pucker of the modified ribose ring of EFdA and ECdA are believed to contribute to inhibition of reverse transcriptase by placing the 3′-OH in a vector, in which phosphotransfer from the incoming nucleotide is inefficient. (Michailidis E, et al., Mechanism of inhibition of HIV-1 reverse transcriptase by 4′-ethynyl-2-fluoro-2′-deoxyadenosine triphosphate, J Biol Chem 284:35681-35691 [2009]; Michailidis E, et al., 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms, J Biol Chem 289:24533-24548 [2014]).
In in vitro HIV replication assays, EFdA is a potent antiretroviral and exhibits comparable antiviral activity against clinical isolates across all subtypes that have been evaluated. It is rapidly anabolized in both lymphoid derived cell lines and in peripheral blood mononuclear cells to the active triphosphate in vitro, and the intracellular half-life of EFdA Triphosphate (EFdA-TP) exceeds 72 hrs. (Stoddart, C. A., Galkina, et al., Oral Administration of the Nucleoside EFdA (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque, Antimicrob Agents Chemother, 2015 July; 59(7): 4190-4198, Published online 2015 May 4).
EFdA has been shown to have efficacy in animal models of HIV infection including humanized mouse models and an SIV infected rhesus macaque model. Pharmacokinetic studies of orally administered EFdA in mouse and rhesus monkey have demonstrated rapid absorption and robust conversion of the nucleoside to the active triphosphate in peripheral blood mononuclear cells (PBMCs). Drug concentrations achieved in both humanized mice and rhesus macaques were efficacious in suppressing viremia when administered to HIV and SIV infected animals, respectively. PBMCs that were isolated from uninfected monkeys 24 hr after drug administration were refractory to SIV infection. (Ibid.) Currently available drug treatments for HIV infection work in combination to suppress viremia, keeping the virus under control. HIV drug therapy is life-long and strict adherence to treatment regimens is critical to maintain viral suppression, reduce the risk of drug resistance, and minimize the risk of transmission. Efficacious and safe, well-tolerated drugs that are easy to take with low dosing frequency have the potential to improve a patient's adherence and long-term treatment success. For prophylaxis against HIV infection, the only currently available pre-exposure prophylaxis (PrEP) treatment approved by the U.S. Food and Drug Administration is TRUVADA® (emtricitabine/tenofovir DF) for prophylaxis against HIV infection in uninfected people.
Currently available orally administered anti-retroviral drugs are dosed once-daily. Less frequent dosing may help to alleviate both practical challenges and the cumulative psychological impact of taking daily HIV medications. Long-acting ARTs may potentially help patients return to a greater sense of normalcy and provide flexibility that could impact the way they live, work, travel, relate to others, and see themselves. Additionally, lessons from other chronic diseases requiring life-long treatment such as osteoporosis and type-2 diabetes have shown that some patients adapt to and may prefer once-weekly over once-daily dosing regimens which can result in improved medication adherence.
It would be desirable to have additional prophylactic therapy options for people at risk of HIV infection, either by administering a single active agent or a combination of active agents. Additionally, it would be desirable to have oral dosing options for HIV therapies, both for treatment and prophylaxis of HIV infection, that could be administered less frequently than dosing on a daily basis, to provide further alternatives for patients.